Protein-tyrosine Phosphatase α Regulates Stem Cell Factor-dependent c-Kit Activation and Migration of Mast Cells*
- Lionel A. Samayawardhenaठand
- Catherine J. Pallen, Recipient of an investigator award from the Child and Family Research Instituteद1
- Departments of ‡Pediatrics and ¶Pathology and Laboratory Medicine and the §Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada
- 1 To whom correspondence should be addressed: 3102-950 West 28th Ave., Vancouver, BC V5Z 4H4, Canada. Tel.: 604-875-2439; Fax: 604-875-2417; E-mail: cpallen{at}interchange.ubc.ca.
Abstract
The role of protein-tyrosine phosphatase α (PTPα) in mast cell function was investigated in tissues and cells from PTPα-deficient mice. Bone marrow-derived mast cells (BMMCs) lacking PTPα exhibit defective stem cell factor (SCF)-dependent polarization and migration. Investigation of the molecular basis for this reveals that SCF/c-Kit-stimulated activation of the Fyn tyrosine kinase is impaired in PTPα-/- BMMCs, with a consequent inhibition of site-specific c-Kit phosphorylation at tyrosines 567/569 and 719. Although c-Kit-mediated activation of phosphatidylinositol 3-kinase and Akt is unaffected, profound defects occur in the activation of downstream signaling proteins, including mitogen-activated protein kinases and Rho GTPases. Phosphorylation and interaction of Fyn effectors Gab2 and Shp2, which are linked to Rac/JNK activation in mast cells, are impaired in PTPα-/- BMMCs. Thus, PTPα is required for SCF-induced c-Kit and Fyn activation, and in this way regulates a Fyn-based c-Kit signaling axis (Fyn/Gab2/Shp2/Vav/PAK/Rac/JNK) that mediates mast cell migration. These defective signaling events may underlie the altered tissue-resident mast cell populations found in PTPα-/- mice.
Footnotes
-
↵2 The abbreviations used are: PTPα, protein-tyrosine phosphatase α; BMMC, bone marrow-derived mast cell; MSCV, murine stem cell virus; SCF, stem cell factor; SFK, Src family kinase; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; PE, phycoerythrin; IL, interleukin; GST, glutathione S-transferase; PBD, p21-binding domain; FACS, fluorescence-activated cell sorter.
-
↵* This work was supported in part by Canadian Institutes of Health Research Grant MOP-49410. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
- Received May 28, 2008.
- Revision received August 7, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
